The present invention relates to derivatives of N-substituted-3-nitro-4-(ureidooxymethyl)benzenesulfonamides, used as sensitizers of hypoxic tumor cells to therapeutic radiation.
Radiation is an effective means of treatment for various types of cancers and tumors. However, it has been found that the effectiveness of radiation is decreased if there is an insufficient supply of oxygen (hypoxia) in the area undergoing treatment. In order to achieve the same proportion of hypoxic tumor cell kill, about three times the radiation dose is required for well-oxygenated cells. Various approaches have been tried to solve this problem including increased oxygen exposure with radiation treatment and the use of drugs that will make hypoxic tumor cells more sensitive to radiation. Halliwell, B. et al., Free Radicals in Biology and Medicine, Oxford, 238-241 (1985). Some drugs which make hypoxic tumor cells more sensitive to radiation operate by inhibiting the production of DNA precursors. Examples of such inhibitors are deoxyadenosine and hydroxyurea. These compounds potentiate chromosome damage initiated by ionizing radiation in mammalian cells. This potentiation most likely reflects an inhibition of DNA repair. Collins, A., Int. J. Radiat. Biol., Vol. 51, No. 6, 971-983 (1987).
Various types of compounds have been utilized to enhance the effects of radiation on hypoxic tumor cells. U.S. Pat. No. 4,603,133 discloses the use of 2-[N-(morpholinoalkyl)amino-sulfonyl]-6-nitrobenzoic acids in radiation treatment. U.S. Pat. No. 4,654,369 discloses the use of 2-(substituted sulfamyl)-6-nitrobenzoic acids which are useful as adjuncts to radiation therapy.
U.S. Pat. No. 4,647,588 discloses 2-(substituted sulfamyl) derivatives of 6-nitrobenzoic acids as having activity in increasing the sensitivity of hypoxic tumor cells to therapeutic radiation. (see also U.S. Pat. Nos. 4,694,020 and 4,731,369).